Macrophage inhibitory cytokine (MIC)-1 is a transforming growth factor-β (TGF-β) superfamily protein. MIC-1 was originally cloned as macrophage inhibitory cytokine-1 and later identified as placental transforming growth factor-β (PTGF-β), placental bone morphogenetic protein (PLAB), non-steroidal anti-inflammatory drug-activated gene 1 (NAG-1), prostate-derived factor (PDF) and growth development factor-15 (GDF-15) (Bootcov et al., 1997; Hromas et al., 1997; Lawton et al., 1997; Yokoyama-Kobayashi et al., 1997; Paralkar et al., 1998). Similar to other TGF-β-related cytokines, MIC-1 is synthesised as an inactive precursor protein, which undergoes disulphide-linked homodimerisation. Upon proteolytic cleavage of the N-terminal pro-peptide, mature MIC-1 is secreted as an approximately 24.5 kDa dimeric protein (Bauskin et al., 2000). Amino acid sequences for MIC-1 are disclosed in WO 99/06445, WO 00/70051, WO 01/81928, WO 2005/113585, Bottner et al. (1999b); Bootcov et al., 1997; Back et al., 2001; Hromas et al. (1997), Paralkar et al., 1998; Morrish et al., 1996; and Yokoyama-Kobayashi et al., (1997). The amino acid sequence for the common or “wild type” mature MIC-1 polypeptide is shown at FIG. 1:
MIC-1 is expressed in several tissues (Moore et al., 2000; Bottner et al., 1999a; Fairlie et al., 1999; Bauskin et al., 2006). For example, Northern blots of human tissues indicate the presence of small amounts of MIC-1 mRNA in the kidney, pancreas and prostate, and large amounts in the placenta (Moore et al., 2000; Fairlie et al., 1999). Further, serum MIC-1 levels have been shown to increase with age in normal, apparently healthy subjects. MIC-1 overexpression has been associated with cancer, particularly prostate cancer (Welsh et al., 2003), and high serum concentrations of MIC-1 are associated with the presence of metastatic disease (Welsh et al., 2003; Brown et al., 2006). Serum MIC-1 is also elevated in chronic inflammatory diseases and predicts atherosclerotic events independently of traditional risk factors. Serum MIC-1 levels are also increased in chronic kidney disease (CKD; Johen et al., 2007).
CKD (also known as chronic renal disease) is characterised by a progressive loss of renal function over a period of months or years through five stages. CKD is initially characterised by mildly diminished renal function with few overt symptoms, which can eventually progress through to the final stage, known as chronic kidney failure (CKF), chronic renal failure (CRF), or end-stage renal disease, that is characterised by a severe illness and usually requires some form of “renal replacement therapy” (eg dialysis or renal transplant). More than 15.5 million adults in the United States of America have moderately severe impairment of renal function, and more than 480,000 are receiving active treatment for end-stage renal disease with more than 100,000 new patients starting treatment annually. Of the patients receiving treatment in 2005, more than 80,000 died.
CKD patients tend to suffer from accelerated atherosclerosis (a chronic inflammatory disease affecting arterial blood vessels), and are more likely to develop cardiovascular disease than the general population. Increased levels of inflammatory markers such as C-reactive protein (CRP) are considered to be a risk factor for acute cardiovascular events for both end-stage renal disease patients and normal populations (Apple et al., 2004). End-stage renal disease is associated with anorexia, weight loss and cachexia. There is thought to be a link between malnutrition and inflammation in renal failure patients with the two conditions often coexisting.
Some patients with end-stage renal disease can survive indefinitely on dialysis; however, many patients are likely to die in the absence of a kidney transplant. Weight loss, a lowered body mass index (BMI) and elevated serum inflammatory markers are considered to be predictors of mortality. However, the contribution of malnutrition and inflammation to disease outcome and the nature of the link between them is ill-defined. There are currently no reliable prospective methods for determining which patients are likely to die in the absence of a kidney transplant, and it is accordingly difficult to determine patients for whom a kidney transplant may be life saving.
The present applicant investigated the relationship between MIC-1 and altered nutrition in CKD and found that MIC-1 levels has clinical utility for prognosing mortality in CKD. The present applicant has also realised that MIC-1 levels can advantageously provide a means for selecting an end-stage renal disease subject for a kidney transplant.